Acetaminophen-induced hepatotoxicity is mediated by a reactive metabolite which is formed in the liver by a minor cytochrome P-450-dependent pathway of drug metabolism. In the major pathways of acetaminophen metabolism nontoxic glucuronide and sulfate conjugates are formed. We have found that diabetic rats are less susceptible than normal rats to acetaminophen hepatotoxicity, and that this increased resistance is associated with an enhanced rated of acetaminophen metabolism. Using in vivo pharmacokinetic techniques, we have determined that the enahnced metabolic rate is largely due to a marked enhancement of the glucuronidation capcity; however, the diabetic animals' capacities for sulfation and glutathione-dependent detoxification are also modestly increased. We now propose to explore the biochemical mechanisms by which the diabetic state causes these effects of acetaminophen metabolism. diabetes is a widespread health problem which causes major alterations in cellular homeostasis. In addition, diabetes can be regarded as a genetically altered nutritional state in that the liver cannot use glucose without prior insulin-dependent phosphorylation. We plan to use the diabetic acetaminophen-overdosed animal model and intact hepatocyte suspensions isolated from such animals to examine the effects of altered cellular metabolism on drug metabolism and toxicity. We propose to extend these studies to determine the relationships between environmentally-induced alterations in cellular metabolism, such as changes in diet, and acetaminophen metabolism and toxicity. Studies in these systems will provide a basis (1) to ask questions about other potential nutritional status-drug interactions, (2) to predict altered drug toxicities and (3) to develop better therapy for acetaminophen overdosage during diabetes and/or malnutrition. Additional studies are planned to determine whether diabetic patients also have an enhanced rate of acetaminophen metabolism. Using the pharmacokinetic techniques developed in the animal model, we will be able to determine the effects of insulin status on the patients' capacities of the individual pathways of drug metabolism.